For storage stability and convenience of handling, pharmaceutical compositions are often formulated as a lyophilized or vacuum dried powder and stored at low temperatures between −10° C. to 4° C. The dry powder is typically reconstituted with a suitable fluid, such as saline or water, prior to administration to a patient. Alternatively, pharmaceutical composition can be formulated as an aqueous solution or suspension that includes a stabilizer to prevent degradation. However, many compounds are difficult to stabilize and there may be a loss of compound or activity during the formulation, reconstitution and/or the period storage. Stability problems can occur as a result of protein denaturation, degradation, dimerization, and/or polymerization. Various excipients have been used with differing degrees of success to try and stabilize an active agent in a pharmaceutical composition. Stabilizers may also be effective in reducing adhesion of the active agent to surfaces, such as the surfaces of laboratory glassware, vessels, the vial in which the pharmaceutical composition is reconstituted or the inside surface of a syringe used to inject the pharmaceutical composition. As well as being able to stabilize an active agent in a composition, an ideal stabilizing agent should have negligible immunogenicity when administered to a human patient.
It has proven particularly difficult to stabilize active agents for cosmetic or topical dermatological preparation. Various types of active agents are useful for the prophylaxis and treatment of cosmetic and dermatological skin changes, such as skin aging and, in particular, aging induced by oxidative or degenerative processes. It is also desirable to prepare preparations that can be administered topically to enhance wound healing or to treat painful neuropathies. Several problems have been encountered in trying to deliver active ingredients through the skin. The size of many active agents makes it difficult for them to penetrate through the skin and it has also proven difficult to stabilize some agents for storage at room temperature.
One example of an active agent that has been postulated to improve the appearance of skin lines is botulinum toxin Type A. However, pure botulinum toxin is extremely susceptible to denaturation due to surface denaturation, heat, and alkaline conditions. Inactivated toxin forms toxoid proteins which may be immunogenic and the resulting antibodies can render a patient refractory to the effects of the toxin. Furthermore, dilution of the toxin complex obtained by culturing, fermentation and purification processes to the much lower toxin concentrations used for a pharmaceutical composition results in rapid detoxification of the toxin unless a suitable stabilizing agent is present. Current formulations of botulinum toxin must be administered within four hours after reconstitution since the toxin molecule is very labile. During this time period, reconstituted botulinum toxin is stored in a refrigerator (4° C.). Breakdown of the toxin into toxoid can induce immune responses to the toxoid that can interfere with subsequent treatments. Current stabilizers that have been used in botulinum toxin formulations are animal derived albumin and gelatin. However, these stabilizers are not able to sufficiently stabilize botulinum toxin for storage at room temperature. Thus there was a specific need for a formulation that could enhance the stability of botulinum toxin and also promote its permeation through the skin.
Several efforts have been made to provide botulinum toxin formulations that can be stabilized and delivered in alternative ways. For example, U.S. Pat. No. 6,585,993 discloses a biocompatible implant for continuous release of a neurotoxin over a treatment period extending from one month to five years. While such an implantable system may be useful for certain situations, such as for the treatment of migraine, this type of implant system is not feasible for the treatment of facial, neck or hand wrinkles.
U.S. Patent Application No. 2004/0247623 suggests a method for the treatment of sensory neuron related distorters through transdermal application of a neurotoxin. This application is particularly directed to a method of treating migraine. The application suggests that botulinum toxin can be administered in a variety of ways.
International Patent Application WO 0158472 describes a pharmaceutical composition comprising botulinum toxin and a polysaccharide. This application teaches that the polysaccharide stabilizes the neurotoxin. However, other studies have shown that saccharides are poor stabilizers for botulinum toxin.
International Patent Application WO 04/060384 discloses a pharmaceutical botulinum toxin composition which includes a sequestration agent. The purpose of the sequestration agent is to prevent the diffusion of the botulinum toxin away from the site of injection. This does not address the need for stable compositions that can be applied to the surface of the skin.
While botulinum toxin can smooth out fine lines and wrinkles for most users, there are several disadvantages associated with its current use. The botulinum toxin must be administered in a doctor's office. The injections can be painful and there may be bruising. Adverse side effects occur in some injection treated patients. Most common side effects for treatment of frown line include droopy eyelids, nausea, flu-like symptoms (fever etc.), headache and respiratory infections. Less frequent reactions may include facial pain, redness at the injection site, and muscle weakness at other sites. Repeated treatments may lead to permanent paralysis of facial muscles leaving the face expressionless. Thus, there was a need for alternative methods of delivering botulinum toxin to the skin.
Another active agent that would be desirable to deliver through the skin is hyaluronic acid (HA). Hyaluronic acid is a naturally occurring high molecular weight polysaccharide that is found in many tissues of the body. Hyaluronic acid has been associated with maintaining moisture in the skin as well as with promoting wound healing and encouraging the formation of vessels. German Patent DE 19805827A describes the protective effect of hyaluronic acid on skin irritations. U.S. Pat. No. 5,728,391 also suggests the use of hyaluronic acid as an agent for treating skin disease. Various formulations for the oral delivery of HA have been suggested. To enhance the effect of HA on the skin, it is desirable to formulate a composition that can be applied topically to the skin. One of the difficulties, however, in trying to increase the permeation of HA in the skin is the size of the molecule. The large polymeric structure that gives HA its beneficial effects also makes it difficult to acquire from outside the body. Thus, there was an unmet need for improved formulations of HA that can be applied topically.
The process that leads to skin aging and wrinkles is complex. A primary cause of wrinkling is a build-up of free radical toxic plaque that binds to collagen and elastin fibers, causing the skin's supportive structure to become inflexible and unhealthy. Laugh lines, smile lines, crow's feet or facial creases appear in areas where repeated muscle movement occurs. Thus, it would be desirable to be able to deliver free radical scavengers to the skin.
Botulinum toxin, hyaluronic acid and anti-oxidants are just a few examples of active agents that it is desirable to deliver to the skin. Other active agents may include enzyme inhibitors, vasodilaters, perflourocarbons, hormones, growth factors, vaccines, drugs, small molecules, amines, peroxides, analgesics and other therapeutic agents. Agents which promote wound healing or reduce pain are also active agents that it would be desirable to administer through the skin.
Thus, there was a need for newer methods for stabilization of active agents for the preparation of topical and cosmetic preparation. There was also a need for improved systems for delivery of active agents to the skin. The present invention addresses those needs.